Cancer of the uterine cervix affects primary young, sexually promiscuous women of low socioeconomic status. Human papillomavirus (HPV) infection has been shown to be the major etiologic factor in the pathogenesis of both carcinoma and its precursor squamous intraepithelial lesions (SIL). Most SIL in normal women regress spontaneously, yet a subset of women undergo progression to invasive cancer. Possible risk factors for development of high grade SIL or cancer include persistent HPV infection, high viral load, increased age, infection with other sexually transmitted diseases (STD), immunodeficiency and HLA type. It is widely hypothesized that intact immune responses to HPV are required for regression of disease and resolution of viral infection, yet this has not as yet been formally demonstrated experimentally. We propose a non-therapeutic prospective study of the role of CMI responses to HPV as well as general CMI status in determining the outcome of genital HPV infection. Women with histopathologically confirmed CIN I or II (N=465) will be recruited and followed at 3-month intervals by Pap smear and colposcopy for 12 months. HPV infection will be identified and typed by both PCR and Southern blot hybridization of DNA from cervicovaginal lavage. Lymphoproliferative CMI responses to HPV 16 E4, E6 & E7 peptides will be done as will mitogen and standard recall antigen responses to assess general CMI status. Endpoint biopsy will be performed at 12 months. Association between regression/persistence of CIN, resolution/persistence of HPV infection and immune responses will be examined. This will provide a unique opportunity to study the role of CMI responses to HPV in determining the natural history of HPV infection. Identification of "protective" epitopes in the E4, E6 & E7 could lead to development of therapeutic HPV vaccines for improved management of women with premalignant disease and prevention of cancer. The major specific aims of this project are: I) To test the hypothesis that deficient CMI responses to HPV 16 E4, E6 or E7 peptides are associated with increased persistence of HPV infection as well as increased viral load, whereas intact CMI responses are associated with resolution of viral infection; 2) To test the hypothesis that deficient CMI responses to HPV 16 peptides are associated with increased persistence or progression of SIL, whereas intact CMI responses are associated with regression of disease; 3) To identify specific E6 or E7 epitopes for which, singly or in combination, positive CMI responses correlate with resolution of HPV infection or regression of SIL; 4). To test the hypothesis that TH1 or TH2 responses as defined by cytokine production by peptide-stimulated lymphocytes (e.g. interferon gamma or IL-4) are associated with resolution of HPV infection and regression of SIL, respectively; 5) To test the hypothesis that CMI responses to specific HPV 16 E4, E6 and E7 epitopes are associated with specific HLA Class II DR-DQ haplotypes as is regression of SIL and resolution of type-specific genital HPV infection.